Method and package for storing a pressurized container containing a drug

ABSTRACT

A method and package for storing a pressurized container which is filled with a drug formulation at a predetermined pressure. The drug formulation includes a mixture of a drug and a propellant. The package which endoses the pressurized container substantially prevents ingression of water vapor and particulate matter into the package while permitting egression of the propellant which may leak from the pressurized container.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No.09/571,388 filed May 15, 2000, now allowed, which is a United StatesNational Phase Application of a continuation-in-part of copending U.S.application Ser. No. 09/290,351, filed on Apr. 12, 1999, the entirecontents of which are incorporated by reference; and for which aninternational application PCT/US99/27851 was filed Nov. 23, 1999; andfor which a U.S. application Ser. No. 09/216,183 was filed Dec. 18,1998.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to a method and package for storinga pressurized container containing a drug.

[0004] 2. Description of the Background Art

[0005] For environmental reasons, there has been a move to replacechlorofluorocarbons (CFCs) (also simply known as “fluorocarbons”) suchas P11, P114 and P12 with hydrofluoroalkane propellants such as HFA-134aand HFA-227. When these hydrofluoroalkane propellants are used as apropellant in a pressurized drug delivery system, various technicalproblems can occur with various drug formulations. Also, it is necessaryto modify the construction of metered dose inhalers for optimumstability and aerosol formation.

[0006] One storing mechanism for a metered dose inhaler (MDI) uses aplastic tube which has a resealable lid to close the tube. Theresealable lid for this tube employs a desiccant to absorb moisturepresent in the tube.

[0007] Such plastic tubes typically increase manufacturing cost andrequire complex and/or expensive manufacturing processes. Such tubes arefrequently bulky in that they require a significant amount of storagespace relative to the size of the container disposed within the plastictube.

[0008] It is well established that non-CFC propellants, especially HFC134a, have a much greater water solubility than the CFC propellantstraditionally used in MDI's. The maximum water solubility in HFC 134a isabout 2200 ppm whereas for CFC 11, 12 and 114, the maximum watersolubilities are about 130 ppm. (See Pischtiak, A. (1999) “Solvay Fluorand Derivate Chemical Data Sheet for CFC and HFC Propellants.”)

[0009] This maximum solubility may be further increased if cosolventssuch as ethanol are used in the formulation. The mechanism of moisturetransport into HFC MDI's has been discussed by Williams, G. andTcherevatchenkoff, A. (1999) “Moisture Transport Into CFC-Free MDI's,”Respiratory Drug Delivery VI, Hilton Head, S.C., USA.

[0010] They concluded that moisture transport is influenced by theelastomeric nature of the valve gaskets as well as the type of HFAformulation and storage conditions employed. It may be appropriate,under certain circumstances to control the ingress of moisture into HFCbased MDI's. A good example of this would be with a hygroscopic drugsubstance. Hence, prevention of moisture ingress is the subject of thisinvention whereby a series of secondary packaging embodimentsdemonstrate advantageously reducing moisture ingress.

SUMMARY OF THE INVENTION

[0011] Accordingly, a need in the art exists for a method and packagefor storing a pressurized container filled with a propellant and a drugwhich substantially prevents ingression of water vapor and particulatematter into the storage package while permitting egression of thepropellant to increase shelf life and performance of the drug and thepropellant. Furthermore, a need exists in the art to provide a methodand package for storing a pressurized container filled with a drug and apropellant which is cost effective and which does not require complexmanufacturing processes and which in turn efficiently envelopes thecontainer to maximize available storage space.

[0012] It is a primary object of the present invention to provide amethod and package for storing a pressurized container, where thepressurized container is filled with a drug and a propellant and wherethe method and package substantially prevent ingression of water vaporand particulate matter into the package while permitting egression ofthe propellant whereby shelf life of the drug is prolonged andperformance of the drug and the propellant are maintained or increased.

[0013] It is a further object of the present invention to provide amethod and package for storing a pressurized container filled with adrug and a propellant where the method and package substantially absorbresidual moisture in the package enclosing the pressurized containerthat is sometimes present on the outer surface of the pressurizedcontainer prior to sealing pressurized container within the package.

[0014] Another object of the present invention is to provide a methodand package for storing a pressurized container including a drug and apropellant which substantially reduces manufacturing costs whilesubstantially reducing the complexity of the manufacturing process ofthe package.

[0015] Another object of the present invention is to provide a methodand package for storing a pressurized container having a drug and apropellant which is easily opened and readily disposable.

[0016] It is a further object of the present invention to provide amethod and package for storing a pressurized container having a drug anda propellant, whereby the propellant preferably meets governmentalguidelines which prohibit the use of CFCs.

[0017] Another object of the present invention is to provide a methodand package for storing a pressurized container which includes a drugand a propellant that does not require complex mechanical devices toenvelope or enclose the pressurized container while substantiallyreducing the amount of storage space needed for the pressurizedcontainer where the package substantially conforms to the shape of thepressurized container. The package is amorphous in shape due to theflexible materials from which it is made.

[0018] Another object of the present invention is to provide a methodand package which form an enclosed volume that stores a pressurizedcontainer in a controlled environment where the pressurized container isisolated from harmful environmental conditions such as humidity, dust,light, and water vapor and other particulate matter.

[0019] Another object of the present invention is to provide and articleof manufacture comprising an integral aerosol dispensing apparatus, adrug formulation, and a flexible package. It is further an object of thepresent invention to provide a drug formulation and carrier withpackaging material having labeling and information relating to thecomposition contained therein and printed thereon. Additionally, afurther object of the invention is to provide an article of manufacturehaving a brochure, report, notice, pamphlet, or leaflet containingproduct information.

[0020] These and other objects of the present invention are fulfilled byproviding a container storage system comprising: a drug formulationcomprising a mixture of a drug and a propellant; a pressurized containerfilled with the drug formulation at a predetermined pressure; and aflexible package for wrapping and sealing the pressurized containerproviding an enclosed volume in which the pressurized container isdisposed, the flexible package being impermeable to water vapor andpermeable to the propellant, the flexible package substantiallypreventing ingression of water vapor and particulate matter into theenclosed volume while permitting egression of the propellant.

[0021] In addition, these and other objects of the present invention arealso accomplished by providing a method of storing a containercomprising the steps of: providing a flexible package material, which isimpermeable to water vapor and permeable to a propellant; filling acontainer with a drug formulation comprising a drug and the propellantat a predetermined pressure; wrapping the container with the flexiblepackage material to form an enclosed volume in which the container isdisposed therein; and sealing the flexible package which in turn closessaid enclosed volume, the flexible package substantially preventingingression of water vapor and particulate matter into the enclosedvolume while permitting egression of the propellant from the enclosedvolume.

[0022] Moreover, these and other objects of the present invention arefulfilled by a packaged metered dose inhaler comprising: an MDIcomprising a container and a drug metering valve, a pressurized drugformulation in the container comprising a propellant and a drugdispersed or dissolved in the propellant; and an overwrap of flexiblematerial enclosing said MDI, the overwrap being made of a moistureimpermeable material.

[0023] Also, these and other objects of present invention areaccomplished by providing an article of manufacture comprising: anaerosol dispensing apparatus for dispensing metered amounts of fluidmaterial from a reservoir, the apparatus comprising a container defininga reservoir, a dispensing valve; a drug formulation located within theaerosol dispensing apparatus comprising a safe and effective medicamentand a pharmaceutically acceptable propellant; and a flexible package forwrapping and sealing the container providing an enclosed volume in whichsaid pressurized container is disposed, the flexible package beingsubstantially impermeable to water vapor and permeable to thepropellant, the flexible package substantially preventing ingression ofwater vapor and particulate matter into the enclosed volume whilepermitting egression of the propellant.

[0024] These and other objects of the present invention are alsoaccomplished by providing a method of improving a product performancecomprising the steps of: providing a flexible package material made ofat least one heat sealable layer, at least one layer of a metal foil,and a protective layer; the flexible package material being impermeableto water vapor and permeable to a propellant; filling a container with adrug formulation comprising a drug and the propellant at a predeterminedpressure; wrapping the container with the flexible package material toform an enclosed volume in which the container is disposed therein; andsealing the flexible package which in turn closes the enclosed volume,the flexible package substantially preventing ingression of water vaporand particulate matter into the enclosed volume while permittingegression of the propellant from the enclosed volume.

[0025] Further scope of applicability of the present invention willbecome apparent from the detailed description given hereinafter.However, it should be understood that the detailed description andspecific examples, while indicating preferred embodiments of theinvention, are given by way of illustration only, since various changesand modifications within the spirit and scope of the invention willbecome apparent to those skilled in the art from this detaileddescription.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The present invention will become more fully understood from thedetailed description given hereinbelow and the accompanying drawingswhich are given by way of illustration only, and thus are not limitativeof the present invention, and wherein:

[0027]FIG. 1 is a top elevational view of the package for storing apressurized container of the present invention;

[0028]FIG. 2 is a side view of the package for storing a pressurizedcontainer of the present invention;

[0029]FIG. 3 is a cutaway bottom view of the package for storing apressurized container of the present invention;

[0030]FIG. 4 is a cross-sectional view of the package for storing apressurized container of the present invention;

[0031]FIG. 5 is a cross sectional view of a metering valve which couldbe used in the present invention; and

[0032]FIG. 6 is a side view of the second container with a product labelwhich is placed over the wrapping means of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] Pressurized Containers

[0034] The pressurized containers useful in the invention include anycontainers in which a drug and a propellant can be stored. Slow leakageof propellant sometimes occurs in metered dose inhalers (MDIs) and thepresent invention is particularly useful in connection with MDIs thatmay have slow leaks.

[0035] The pressurized container is preferably an MDI or an MDI can. Theterm “metered dose inhaler” or “MDI” means a unit comprising a can, acrimped cap covering the mouth of the can, and a drug metering valvesituated in the cap, while the term “MDI system” also includes asuitable channeling device. The term “MDI can” means the containerwithout the cap and valve. The term “drug metering valve” or “MDI valve”refers to a valve and its associated mechanisms which delivers apredetermined amount of drug formulation from an MDI upon eachactivation. The channeling device may comprise, for example, anactuating device for the valve and a cylindrical or cone-like passagethrough which medicament may be delivered from the filled MDI can viathe MDI valve to the nose or mouth of a patient, e.g. a mouthpieceactuator. The relation of the parts of a typical MDI is illustrated inU.S. Pat. No. 5,261,538 incorporated herein by reference. An exemplaryMDI is disclosed in WO 96/26755, the entire contents of which is herebyincorporated by reference. Other exemplary pressurized containers foruse in MDIs are disclosed in WO 96/32151, WO 96/32345, WO 96/32150 andWO 96/32099.

[0036] The pressurized container 34 is preferably a vial made fromaluminum. However, other materials are not beyond the scope of thepresent invention. Other materials for the pressurized container 34include, but are not limited to, ferrous alloys, non-ferrous alloys,such as stainless steel, ceramic materials, polymers, compositematerials, and mixtures thereof. Suitable containers which contain apolymeric coating on the inside thereof are disclosed in WO 96/32151.

[0037] Most often the MDI can and cap are made of aluminum or an alloyof aluminum, although other metals not affected by the drug formulation,such as stainless steel, an alloy of copper or tin plate, may be used.An MDI can may also be fabricated from glass or plastic. Preferably,however, the MDI cans employed in the present invention are made ofaluminum or an alloy thereof. Advantageously, strengthened aluminum oraluminum alloy MDI cans may be employed. Such strengthened MDI cans arecapable of withstanding particularly stressful coating and curingconditions, e.g., particularly high temperatures, which may be requiredfor certain fluorocarbon polymers. Strengthened MDI cans which have areduced tendency to malform under high temperatures include MDI canscomprising side walls and a base of increased thickness and MDI canscomprising a substantially ellipsoidal base (which increases the anglebetween the side walls and the base of the can), rather than thehemispherical base of standard MDI cans. MDI cans having an ellipsoidalbase offer the further advantage of facilitating the coating process.

[0038] The MDI cans include MDI cans supplied by Presspart of Cary,N.C., USA or the United Kingdom, or by Neotechnic of the United Kingdom.The MDI cans typically have a neck diameter of 20 millimeters, althoughany suitable neck diameter may be used and can vary in height from 30millimeters to 60 millimeters.

[0039] The drug metering valve consists of parts usually made ofstainless steel, a pharmacologically inert and propellant resistantpolymer, such as acetal (polyoxymethylene), polyamide (e.g., Nylon®),polycarbonate, polyester, fluorocarbon polymer (e.g., Teflon®) or acombination of these materials. Additionally, seals and “O” rings ofvarious materials (e.g., nitrile rubbers, polyurethane, acetyl resin,fluorocarbon polymers), or other elastomeric materials are employed inand around the valve.

[0040] The preferred MDI valves have typical metering chamber volumes of25 to 63 microlitres. The valves preferably have a ferrule skirt to suita 20 mm neck diameter can. Typical suppliers of MDI valves includeValois Pharm, France; Bespak of Europe or the United Kingdom; orNeotechnic, United Kingdom.

[0041] Drugs

[0042] Preferred drugs (also referred to as “medicaments”) and drugcombinations are disclosed in WO 96/32151, WO 96/32345, WO 96/32150 andWO 96/32099, the entire contents of which are hereby incorporated byreference. These drugs include, for example, fluticasone propionate or aphysiologically acceptable solvate thereof, beclomethasone dipropionateor a physiologically acceptable solvate thereof, salmeterol or aphysiologically acceptable salt thereof and albuterol or aphysiologically acceptable salt thereof. Medicaments may be selectedfrom, for example, analgesics, e.g. codeine, dihydromorphine,ergotamine, fentanyl or morphine, anginal preparations, e.g. diltiazem;antiallergics, e.g. cromoglycate, ketotifen or nedocromil;antiinfectives e.g. cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines and pentamidine; antihistamines, e.g.methapyrilene; anti-inflammatories, e.g. beclomethasone (e.g. thedipropionate), flunisolide, budesonide, tipredane or triamcinoloneacetonide; antitussives, e.g. noscapine; bronchodilators, e.g.salbutamol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol,isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, reproterol, rimiterol, terbutaline, isoetharine,tulobuterol, orciprenaline, or(-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropineor oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone;xanthines e.g. aminophylline, choline theophyllinate, lysinetheophyllinate or theophylline; and therapeutic proteins and peptides,e.g. insulin or glucagon. It will be clear to a person skilled in theart that, where appropriate, the medicaments may be used in the form ofsalts (e.g. as alkali metal or amine salts or as acid addition salts) oras esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) tooptimise the activity and/or stability of the medicament and/or tominimize the solubility of the medicament in the propellant.

[0043] Additionally, any suitable combination of drugs can be used inthe present invention. For example, Seretide (fluticasone and Serevent)can be used in the present invention.

[0044] Propellants

[0045] “Propellants” used herein mean pharmacologically inert liquidswith boiling points from about room temperature (25° C.) to about −25°C. which singly or in combination exert a high vapor pressure at roomtemperature, including CFCs such as Freon and hydrofluorocarbons. Uponactivation of the MDI system, the high vapor pressure of the propellantin the MDI forces a metered amount of drug formulation out through themetering valve then the propellant very rapidly vaporizes dispersing thedrug particles. The propellants used in the present invention are lowboiling fluorocarbons; in particular, hydrofluorocarbons orhydrofluoroalkanes such as HFA-134a and HFA-227. The invention isparticularly useful with propellants (including propellant mixtures)which are more hygroscopic than P11, P114 and/or P12 such as HFA-134aand HFA-227.

[0046] Additional Components of the Drug Formulation

[0047] The MDIs taught herein are particularly useful for containing anddispensing inhaled drug formulations with hydrofluoroalkane propellantssuch as 134a with little, or essentially no, excipient and which tend todeposit or cling to the interior walls and parts of the MDI system. Incertain cases, it is advantageous to dispense an inhalation drug withessentially no excipient, e.g., where the patient may be allergic to anexcipient or the drug reacts with an excipient.

[0048] Drug formulations for use in the invention may be free orsubstantially free of formulation excipients, e.g., surfactants andcosolvents, etc. Such drug formulations are advantageous since they maybe substantially taste and odor free, less irritant and less toxic thanexcipient-containing formulations. Thus, a preferred drug formulationconsists essentially of a drug, or a physiologically acceptable salt orsolvate thereof, optionally in combination with one or more otherpharmacologically active agent, and a fluorocarbon propellant.

[0049] Further drug formulations for use in the invention may be free orsubstantially free of surfactant. Thus, a further preferred drugformulation comprises or consists essentially of a drug (or aphysiologically acceptable salt or solvate thereof), optionally incombination with one or more other pharmacologically active agents, afluorocarbon propellant and 0.01 to 5% w/w based on the propellant of apolar cosolvent, which formulation is substantially free of surfactant.Preferred propellants are 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof, and especially1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane.However, the drug formulation may contain any additional excipientswhich are necessary or desirable to prepare a suitable drug formulation.

[0050] The term “excipients” as used herein means chemical agents havinglittle or no pharmacological activity (for the quantities used) butwhich enhance the drug formulation or the performance of the MDI system.For example, excipients include but are not limited to surfactants,preservatives, flavorings, antioxidants, antiaggregating agents, andcosolvents, e.g., ethanol and diethyl ether.

[0051] Suitable surfactants are generally known in the art, for example,those surfactants disclosed in European Patent Application No. 0327777.The amount of surfactant employed is desirably in the range of 0.0001%to 50% w/w ratio relative to the drug, in particular 0.05 to 5% w/wratio.

[0052] A polar cosolvent such as C₂₋₆ aliphatic alcohols and polyols,e.g., glycerol, ethanol, isopropanol and propylene glycol, preferablyethanol, may be included in the drug formulation in the desired amount,either as the only excipient or in addition to other excipients, such assurfactants. Suitably, the drug formulation may contain 0.01 to 5% w/wbased on the propellant of a polar cosolvent, e.g., ethanol, preferably0.1 to 5% w/w, e.g., about 0.1 to 1% w/w.

[0053] Flexible Packaging Materials

[0054] The flexible packaging material can be any material which isimpervious to or substantially impervious to moisture. The packagingmaterial is preferably permeable to propellants such as HFA-134a and/orHFA-227 whereby if the propellant slowly leaks from the pressurizedcontainer, the propellant will slowly pass, by diffusion or otherwise,through the packaging material.

[0055] For ease of manufacturing, and in order to provide the necessaryproperties to the packaging material, the flexible packaging materialpreferably comprises a non-thermoplastic substrate (such as a metalfoil) and a heat sealable layer disposed thereon, and an additionalprotective layer, such as a polymer film of polyester. The heat sealablelayer is usually disposed on the inner surface of the assembled package.The additional protective layer is usually disposed on the surfaceopposite the heat sealable layer. An example of a particularly usefulfoil laminate is a polyester film adhesively laminated to aluminum foiladhesively laminated to Ionomer (SURLYN™) film, for example, 12 μpolyester/9 μ aluminum/50 μ ionomer film supplied by Lawson MardonSingen (LMS).

[0056] The substrate is preferably formed from aluminum foil. However,other metals for the substrate include, but are not limited to, tin,iron, zinc, or magnesium formed on a sheet by vacuum deposition orsputtering and a carboxyl group-containing polyolefin layer formed onthe metal layer by lamination.

[0057] The heat sealable layer can be formed from any thermoplastic orthermosetting material such as an ionomer resin, polyolefin, orcycloolefin copolymer. Ionomer resins typically include ionically cross-linked ethylene-methacrylic acid and ethylene acrylic acid copolymers.Properties which distinguish these ionomers resins from other polyolefinheat-sealed polymers are high clarity, high impact resistance, low hazein lamination, tear resistance, abrasion resistance, solid statetoughness, and moisture imperviousness. In the preferred embodiment, theheat sealable layer is made out of SURLYN™ (an ionomer resin) or a formof polyethylene to provide sufficient heat sealing properties.

[0058] The outer protective layer, if present, can be formed of anymaterial as long as the final laminate has the requisite properties.

[0059] Preferably, the protective layer (e.g., polyester) is adhesivelylaminated to the substrate (e.g., aluminum) and the substrate layer inturn is adhesively laminated to the heat sealable layer (e.g., theionomer film or SURLYN™ (an ionomer resin)).

[0060] Preferred exemplary thicknesses of the three layers include aprotective layer 1 to 40, preferably 4 to 30, more preferably 10 to 23microns, and most preferably 12 microns; a substrate layer of 1 to 100,preferably 3 to 70, more preferably 5 to 50 microns, more preferably 6to 20 microns, and most preferably 9 microns. For the heat sealablelayer, preferred exemplary thicknesses include thicknesses of 1 to 100,preferably 5 to 70, more preferably 10 to 60, more preferably 20 to 55microns, and most preferably 50 microns.

[0061] Adhesives may be used to join the respective layers of materialstogether. The adhesive layers are typically substantially smaller inthickness relative to the thickness of the substrate, heat sealableand/or protective layers which they bond.

[0062] The number, size, and shape of the layers are not limited tothose layers shown in the drawings. Any number of layers with relativeareas of any size and predetermined thicknesses may be used so long asthe flexible package forms an enclosed volume which substantiallyprevents ingression of water vapor and particulate matter into theenclosed volume while permitting egression out of the enclosed volume ofany propellant leaving the pressurized container. The size, shape, andnumber of layers of the package is typically a function of the size andcontents of the pressurized container which includes a drug and apropellant.

[0063] The package is believed to operate similarly to a virtual one-wayvalve due to the composition of the layers and due to the transmissionrate of water vapor molecules into the enclosed volume relative to thetransmission rate of gas molecules of a propellant, such as ahydrofluoroalkane, out of the enclosed volume. The package permits thepropellant in the pressurized container to diffuse out of the enclosedvolume while substantially preventing water vapor and other particulatematter from entering the enclosed volume. Excess or leakage of thepropellant is permitted to egress from the package. The virtual one-wayvalve function of the package prevents or minimizes the chance of anysudden ruptures or prevents or minimizes unexpected expulsion of thepropellant during opening of the package.

[0064] Moisture Absorbing Materials

[0065] The moisture absorbing material is preferably a silica geldesiccant sachet. However, other vapor or moisture absorbing mechanismsare not beyond the scope of the present invention. Other vapor ormoisture absorbing materials include desiccants made from inorganicmaterials such a zeolites and aluminas. Such inorganic materials ofvapor or moisture absorbing materials have high water absorptioncapacities and favorable water absorption isotherm shapes. The waterabsorption capacity of such materials typically varies from 20 to 50weight percent.

[0066] In the preferred embodiment, the absorbing material is a MINIPAX®supplied by Multisorb Technologies in the United States and Silgelac inEurope (silica gel packaged inside TYVEK®, which is a nylon mesh bondedwith a microporous polyurethane). Other exemplary moisture absorbingmaterials include, but are not limited to, alumina, bauxite, anhydrous,calcium sulfate, water-absorbing clay, activated bentonite clay, amolecular sieve, or other like materials which optionally include amoisture sensitive color indicator such as cobalt chloride to indicatewhen the desiccant is no longer operable. While in the preferredembodiment of the present invention, the package is designed tosubstantially prevent ingression of water vapor and particulate matterinto the enclosed volume, the moisture absorbing material is placedwithin the enclosed volume in order to absorb any residual moisturepresent in the atmosphere or on the external surface of the pressurizedcontainer or mouthpiece or a combination thereof, prior to sealing thepackage.

[0067] The desiccant should be present in an amount sufficient to absorbany residual moisture inside the package or which might escape frominside the pressurized container. When silica gel is used, 1 g to 10 gof silica gel is sufficient for a typical MDI. Moreover, the desiccantshould be present in an amount sufficient to absorb any moisture thatpossibly ingresses from the external environment.

[0068] It is also possible to place the desiccant inside the container,either loose in the canister or as part of an assembly attached to thecanister.

[0069] The Container Storage System

[0070] Referring in detail to the drawings and with particular referenceto FIG. 1, a container storage system (or packaged product) 20 is shown.The container storage system 20 includes a package or wrapping 22 thatemploys multi-layers of material 24, 26, 28. (See FIG. 4.) The package22 further includes fin seams 30, 32 which are disposed along twoparallel side edges of the package and along a single longitudinal edgeof the package 22.

[0071] The number and type of fin seams 30, 32 are not limited to thetypes shown in the drawings. The package 22 can include additional seamsor significantly fewer seams such as a continuous single seam. Theorientation of the seams 30, 32 is not limited to the orientation shownin the drawings. The orientation of the seams 30, 32 is typically afunction of the sealing device and such seams may be oriented in amanner which substantially increases manufacturing efficiency. Duringmanufacture, the longitudinal seam 30 may be formed first by heatsealing and the two end seams 32 may then be formed by heat sealing toclose the package. Other types of seams include, but are not limited to,gusset type seams which include excess material which providesexpansibility, stitched type seams, or mechanically crimped seams, andother like structures.

[0072] The container storage system includes a pressurized container 34which is preferably part of an MDI 36 (see FIG. 3). While the preferredpressurized container 34 is part of an MDI 36, other devices whichinclude pressurized containers 34 are not beyond the scope of thepresent invention.

[0073] The fin seams 30 and 32 are formed by a conventional heat sealingdevice which mechanically crimps sides of the package 22 together whilesimultaneously providing heat to the sides 30, 32. The heat sealingdevice typically has electrical heater elements shaped to produce thepattern of the fin seams 30, 32 where the fin seams include multipleridges 38. The sealing mechanism of the container storage system 20 ofthe present invention is not limited to heat sealing devices. Othersealing devices include, but are not limited to, glue sealing machines,sonic welding machines, electron beam radiation machines, and other likesealing devices.

[0074] As seen in FIGS. 1 and 2, the package 22 preferably has asubstantially rectangular configuration with a substantially ellipticalcross section, however, other shapes of the package 22 are not beyondthe scope of the present invention. Other shapes include, but are notlimited to circular, square, triangular, trapezoidal, pentagonal,hexagonal, octagonal, and other like shapes. The shape of the package 22is preferably a function of the shape of the enclosed pressurizedcontainer 34 as well as the amount and type of storage space since thepackage 22 is made from flexible materials as will be described infurther detail below.

[0075] As seen in FIG. 3, the package 22 provides an enclosed volume 40in which the pressurized container 34 is disposed therein. The size ofthe enclosed volume 40 can be adjusted according to the size of thepressurized container 34 and related parts thereto. Preferably, theenclosed volume 40 is of a size which permits relative ease of closingrespective sides and layers 24, 26 and 28 without substantial stretchingof the package 22. The enclosed volume 40 may be substantially evacuatedprior to formation of the fin seams 30, 32 to substantially reduce anywater vapor being present in the enclosed volume 40. The enclosed volume40 may be evacuated to such a degree that the enclosed volume 40 is avacuum region around the pressurized container 34. While the enclosedvolume 40, may remain constant, its relative shape may change accordingto shifting of the pressurized container 34 disposed within the enclosedvolume 40.

[0076] The amorphous shape of the enclosed volume 40 is attributed tothe flexible materials which make up the layers 24, 26, 28 of thepackage 22 which will be discussed in further detail below. The enclosedvolume can be varied in size such that it substantially conforms to theshape of the pressurized container 34 and any related parts thereto orsuch that the enclosed volume 40 is larger than the pressurizedcontainer 34, as shown in FIG. 3. When the enclosed volume is of a sizewhich is substantially equivalent with the surface area of thepressurized container 34 and related parts, the layers 24, 26, and 28 ofmaterial substantially conform to the shape of the pressurized canister34 and related parts. The package is preferably placed in a separate,more rigid container, such as a paperboard or cardboard box 74 (See FIG.6) typically used in the pharmaceutical industry. The package may expandduring storage due to slow leakage of the propellant from thepressurized container. In this situation, the shape of the package mayconform to some extent to the internal shape of the rigid container ifthe volume of the rigid container is just slightly larger than theexpanded volume of the flexible package.

[0077] In one exemplary embodiment, FIG. 3 shows the pressurizedcontainer 34 to be connected to a nozzle 42 by a valve stem 44. Thepressurized container 34 is preferably an aluminum metal vial having ametering valve 60 (See FIG. 5) disposed therein which is connected tothe valve stem 44. The pressurized container 34 is not limited to thenozzle 42 and valve stem 44 shown and the metering valve 60. While thepressurized container 34 preferably includes a metering valve, othervalve systems are not beyond the scope of the present invention. Othervalve systems include, but are not limited to, wedge gate valve systems,double-disc gate valve systems, globe and angle valve systems, swingcheck valve systems, end cock valve systems, and other like valvesystems. Since the pressurized container 34 is preferably part of anMDI, the valve design is typically a function of providing apredetermined dosage or amount of the drug contained within thepressurized container 34 to a user.

[0078] The nozzle 42 is typically fixably secured to the mouthpiece 46.However, other embodiments where the nozzle 42 is separate or detachedfrom the mouthpiece 46 is not beyond the scope of the present invention.The pressurized canister 34, the nozzle 42, and the mouthpiece 46together comprise an MDI 36.

[0079] As seen in FIG. 3, nozzle 42 is in fluid communication with themouthpiece 46 so that upon movement of the pressurized containerrelative to the mouthpiece 46 in a direction where the pressurizedcontainer 34 moves towards the nozzle 42 fixed to one side of themouthpiece 46, a metered dosage or predetermined amount of the drug andpropellant contained within the pressurized container 34 is released.Such a combination of the fixed nozzle 42, mouthpiece 46, valve stem 44,and pressurized container 34 form an MDI 36 as outlined above.

[0080] The MDI 36 can be packaged by the flexible packaging material 22in either an assembled state (valve stem 44 fixed to nozzle 42) or adisassembled state (valve stem 44 detached from nozzle 42). In apreferred embodiment, the moisture absorbing material 50 lays adjacentto the mouthpiece 46 in a loose or free flowing manner. Alternatively,the moisture absorbing material can be secured to the inside of theflexible package. In another alternative embodiment, the moistureabsorbing material may be disposed within the container 34 or attachedto a bracket structure such as a ring which is fastened to the container34.

[0081] In one possible embodiment, the moisture absorbing material maybe attached to the external surface of the mouthpiece 46 by a fasteningdevice such as a rubber band 48. The fastening device 48 is preferably aremovable elastic mechanism such as a rubber band. However, otherfastening devices are not beyond the scope of the present invention.Other fastening devices include, but are not limited to, adhesives,adhesive tapes, shrink-wrap plastic, fasteners such as screws, nails, orrivets, compartments which are part of the mouthpiece housing 46, andother like attachment devices.

[0082] The mouthpiece 46 substantially encloses pressurized container34. The mouthpiece 46 is preferably simple in structure so thatmanufacturing efficiency and economy is substantially increased.However, other mouthpieces 46 are not beyond the scope of the presentinvention. Other mouthpieces include, but are not limited to, relativelymovable mouthpieces with multiple parts, mouthpieces which also includea protective casing substantially surrounding the mouthpiece protectingthe mouthpiece 46 from damage due to shock, and other like mouthpiecestructures.

[0083] The pressurized container 34 may be held in the mouthpiece 46 byribs or projections (not shown) extending from walls of the mouthpieceso that the pressurized container 34 is in a press-fit engagement withthe mouthpiece 46. The valve stem 44 also provides a secure connectionto the nozzle 42 which is fixedly secured to the mouthpiece 46. Othertypes of supporting mechanisms which hold the pressurized container 34within the mouthpiece 46 are not beyond the scope of the presentinvention. Other types of securing or supporting mechanisms include, butare not limited to, fasteners such a screws, nails, or rivets,adhesives, mouthpieces with a female or male locking/keying mechanismwhich engages with a predetermined shape of the pressurized container,or other like supporting structures.

[0084] In the preferred embodiment of the invention, the supportmechanisms, such as ribs or projections (not shown) of the mouthpiece 46are designed for manufacturing efficiency which in turn reduces cost ofthe overall manufacturing process of the mouthpiece 46. The mouthpiece46 is preferably made of plastic, however other materials are not beyondthe scope of the present invention. Other materials for the mouthpiece46 include, but are not limited to, ferrous alloys, non-ferrous alloys,ceramic materials, and composite materials and any mixtures thereof.Similar to the mouthpiece, the valve stem 44 is preferably made ofplastic, but other materials are not beyond the scope of the presentinvention. Other materials for the valve stem 44 include, but are notlimited to, ferrous alloys, non-ferrous alloys, ceramic materials,composite materials, and any mixtures thereof.

[0085] The pressurized container 34 preferably includes a liquid storedwithin the pressurized container 34 at a predetermined pressure. Theliquid preferably includes a drug dispersed or dissolved therein such assalmeterol or fluticasone propionate.

[0086] In FIG. 4, a cross-sectional view of the package 22 is shown. Finseams 32 include two peripheral edges 52, 54 of the flexible packagingmaterial. The flexible packaging material comprises a first layer 24, asecond layer 26, and a third, preferably heat sealable, layer 28 ofmaterial. The first layer 24 and third layer 28 are preferably made frompolymers. The first layer 24 is preferably made out of polyester whilethe third layer 28 is preferably made out an ionomer resin. The secondlayer 26 is preferably made of a metal foil. In the preferredembodiment, the metal foil is made out of aluminum. In an alternativeembodiment, the heat sealable layer is a polyethylene film.

[0087] As stated above, preferably, the protective layer (e.g.,polyester) is adhesively laminated to the substrate (e.g., aluminum) andthe substrate layer in turn is adhesively laminated to the heat sealablelayer (e.g., the ionomer film or SURLYN™ (an ionomer resin) or apolyethylene film).

[0088] Preferred exemplary thicknesses of the three layers include aprotective layer made of a polyester film having a thickness of 1 to 40,preferably 4 to 30, more preferably 10 to 23 microns, and mostpreferably 12 microns; a substrate layer made of aluminum having athickness of 1 to 100, preferably 3 to 70, more preferably 5 to 50microns, more preferably 6 to 20 microns, and most preferably 9 microns.For the heat sealable layer, an ionomer film is used having a preferredexemplary thicknesses of 1 to 100, preferably 5 to 70, more preferably10-60, more preferably 25-55 microns, and most preferably 50 microns. Inan alternative embodiment, a heat sealable layer of polyethylene film isused having a preferred thicknesses of 1 to 100, preferably 5 to 70,more preferably 10-60, more preferably 20-50 microns, and mostpreferably 50 microns.

[0089] Preferred exemplary embodiments include a polyester film as theprotective layer having a thickness ranging from 12 to 23 microns. Thepolyester film is laminated to an aluminum foil as the substrate layerhaving a thickness ranging from 6 to 20 microns. The aluminum foil islaminated to a sealing film such as either an inomer film having athickness ranging from 25 to 50 microns or a polyethylene film having athickness ranging from 20 to 50 microns.

[0090] Alternative preferred embodiments include aluminum metalizedpolyester film laminated to a heat sealable layer as outlined above.Another embodiment includes a silicon oxide coplated polyester filmlaminated to a heat sealable layer as outlined above. Yet, in anotherembodiment, a polyester film as a protective layer having a thicknessranging from 12 to 30 microns is laminated to an aluminum foil substratelayer having a thickness ranging from 6 to 20 microns, the aluminum foilbeing laminated to a polyester film of 12 to 30 microns which islaminated to a heat sealable layer as outlined above. In anotherembodiment, a polypropylene film as a protective layer having athickness ranging from 15 to 30 microns is laminated to an aluminum foilsubstrate layer having a thickness ranging from 6 to 20 microns, and thealuminum foil is laminated to a heat sealable layer as outlined above.The laminates of the present invention can be adhesively laminated orextrusion laminated.

[0091] The general structure for the preferred embodiment of the presentinvention is as follows: OUTSIDE ENVIRONMENT, POLYESTER FILM 24,ALUMINUM FOIL 26, IONOMER FILM 28, ENCLOSED VOLUME 40, IONOMER FILM 28,ALUMINUM FOIL 26, POLYESTER FILM 24, OUTSIDE ENVIRONMENT. (See FIG. 4.)

[0092] The lines in the drawings which show the boundaries betweenrespective layers 24, 26, and 28 may be considered as adhesive layers ifadhesives are used to join the respective layers. In other words, forexample, the line separating protective layer 24 from the metal foillayer 26 may be interpreted as an adhesive, if an adhesive is used tojoin these layers 24, 26.

[0093]FIG. 5 shows an exemplary fluid dispensing apparatus 36 containinga metered aerosol dispensing valve 60 which dispenses metered amounts offluid material 76 from a reservoir 64. The fluid dispensing apparatus(or metered dose inhaler) may also be packaged as an article ofmanufacture (shown in FIGS. 2, 3, or 6) comprising an aerosol dispensingvalve 60 of the present invention, an integral or additional dispensingapparatus, and a safe and therapeutically effective amount of amedicament in a pharmaceutically acceptable carrier, particularly apropellant. The medicament and carrier can also contain othermedications and various excipients.

[0094] The packaging material of the article of manufacture may alsohave labeling 55 and information relating to the composition containedtherein and/or printed thereon, such as by an adhesive label secured tothe exterior of the flexible package. Additionally or alternatively, thearticle of manufacture of the present invention may have a brochure,report, notice, pamphlet, or leaflet 65 containing product information.This form of product information is sometimes, in the pharmaceuticalindustry, called the “package insert.” A package insert 65 may beattached to or included with the article of manufacture. The packageinsert will usually be provided inside the box 74 but outside theflexible package. The package insert 65 and any article of manufacturelabeling provides information relating to the composition and use of theproduct. This information and labeling provides various forms ofinformation utilized by health care professionals and patients thatdescribes the composition, the dosage, the use, and various otherparameters of the medicament required by regulatory agencies, such asthe United States Food and Drug Administration.

[0095]FIGS. 5 and 6 show an article of manufacture including packagingmaterial 22, a fluid dispensing apparatus or MDI 34 for dispensingmetered amounts of fluid material 76 from a reservoir 64. In oneexemplary embodiment, the fluid dispensing apparatus 34 can include acontainer 34 defining a reservoir 64, and a dispensing valve 60. Thedispensing valve 60 can include a metering chamber body 62, defining ametering chamber 66 and having one or more metering chamber ports 68;and a stem 42 allowing for slideable movement within the meteringchamber body 62. The stem 42 has a dispensing passage 70 and isconnected to a sealing segment 72 allowing for slideable movement overthe one or more metering chamber ports 68. The present invention is notlimited to the fluid dispensing apparatus shown in FIG. 5 and caninclude other types of fluid dispensing devices.

[0096] The stem 42 and sealing segment 72 can be moveable such that in afirst position the metering chamber 66 is fluidically isolated from thedispensing passage 70, and the metering chamber 66 is in fluidiccommunication with the reservoir 64 through the one or more meteringchamber ports 68 and the dispensing passage 70. In a second position (asshown in FIG. 5), the metering chamber 66 is in fluidic communicationwith the dispensing passage 70; and the metering chamber 66 isfluidically isolated from the reservoir 64 by the sealing segment 72occluding the one or more metering chamber ports 68 and the stemoccluding the dispensing passage 70. Also shown in FIG. 5, is fluidmaterial 76 containing a safe and effective medicament and apharmaceutically acceptable carrier or diluent or propellant.

[0097] The dispensing valve 60 can further include an upper sealingsleeve 78 and lower sealing sleeves 80 and 80′. Stem 42 is positionedfor slideable movement within metering chamber 7 through the lower andupper aperture containing lower sealing sleeves 80 and 80′ and the uppersealing sleeve 78.

[0098] Flange 82 and spring 84 define the limits of travel for stem 42.Within these limits of travel, the stem 42 occupies an infinite numberof positions which include the above mentioned first and secondpositions. In FIG. 5, stem 42 is biased toward the upper sealing sleeve78 in the second position by physical force exerted by a user

[0099] In FIG. 6, a box 74 encloses the container storage system 20. Onthe exterior of the box 74, a label 55 is disposed which providesinformation relating to the composition contained within the MDI. Thelabel 55 may be located on any side of the box 74, that is mostbeneficial to the user. Further, as mentioned above, a package insert 65may be disposed within the box 74 and outside the container storagesystem 20.

[0100] The present invention also provides a method of storing acontainer 34 including the steps of providing a flexible package 22where the package 22 includes layers 24, 26, and 28 of material whichare collectively impermeable to water vapor and permeable to vaporizedpropellant.

[0101] The method includes the step of filling the container 34 with theliquid propellant at a predetermined pressure and wrapping the container34 with the flexible package 22 to form an enclosed volume 40 in whichthe first container 40 is disposed therein.

[0102] The method further includes sealing the flexible package 22 whichin turn closes the enclosed volume 40, so that the flexible package 22substantially prevents ingression of water vapor and particulate matterinto said enclosed volume 40 while permitting egression of saidvaporized propellant, whereby shelf life and performance of the drug andthe propellant are increased. The packaged product can be stored forprolonged periods of time such as 1 month or more, 3 months or more or 6months or more at temperatures such as 25, 30 or 40° C. and at relativehumidities of 60 or 75% while maintaining acceptable product properties.

[0103] The invention further includes method steps drawn to providing amaterial 50 for absorbing moisture in the enclosed volume 40 anddisposed adjacent to the container 34.

[0104] Examples and Comparative Tests/Analysis

[0105] In order to evaluate the effectiveness of the method and packagefor storing a pressurized canister of the present invention, shelf-lifetests were carried out upon packages 22 which contained MDIs such assalmeterol/HFA-134a inhalers, Albuterol/HFA-134a, and FluticasonePropionate/HFA-134a inhalers. A first shelf-life test ofAlbuterol/HFA-134a inhalers showed that by placing an MDI into thepackage 22 containing silica gel desiccant or an absorbing mechanism 50,it was possible to substantially reduce the amount of moistureingression (measured in Parts Per Million or PPM) into the inhaler afterthree months of storage at 40° C. and at 85% relative humidity. SeeTable 1. TABLE 1 1 month 3 months Sample Initial @40° C./85% RH @40°C./85% RH Control (non 35 ppm 330 ppm 446 ppm overwrapped inhaler)Inhaler sealed in foil 35 ppm 106 ppm 178 ppm overwrap with 10 g silicagel desiccant Inhaler stored in 35 ppm 158 ppm 198 ppm Zantac Efferdosetube

[0106] Also included in Table 1 is data for MDIs which are stored in theprior art type tube containers. The prior art type tubes included aZANTAC™ EFFERDOSE™ tube. This type of tube is a plastic tube whichcontains silica gel desiccant. The silica gel is disposed in aresealable lid that closes the tube. This tube construction is similarto that used for a Schering product, VANCERIL™ double strength.

[0107] A second test was performed and the results indicate that thereduction of moisture content within the package 22 can improve overallproduct performance of the liquid contained within the pressurizedcontainer 34, where the liquid includes an asthma treating drug and apropellant. In the second test, the experiment was performed where agednon-overwrapped salmeterol/HFA-134a inhalers were compared to MDIsprovided in the package 22. The experiment included non-overwrappedinhalers which were stored for three months at either 30° C./60%relative humidity or 40° C./75% relative humidity. The non-overwrappedinhalers were then placed in a desiccator containing phosphorouspentoxide. The non-overwrapped inhalers were then tested for moisturecontent and fine particulate mass (FPM—the moisture sensitive productperformance test over the period of inhaler storage). The results ofthis test are presented in Table 2. TABLE 2 30° C./60% RH 40° C./75%Moisture content, FPM, Moisture content, FPM, Time PPM Mcg PPM McgInitial 92 10.3 92 10.3  1 month non Not Not 412 8.2 overwrapped testedtested 3  month non 463 7.9 616 6.2 overwrapped  6 weeks storage 233 8.9298 7.4 13 weeks storage 151 9.4 230 8.0

[0108] The data in Table 2 shows that loss and product performance (lossin FPM, for salmeterol) is directly related to change in moisturecontent. The results indicated that product performance of MDIs isreversible, although not 100% reversible. Therefore, if moisture causesloss in product performance, it is possible to retrieve and improve theproduct performance by removing moisture from the MDI during storage.Such is the result with the package 22 of the present invention. Thus,the data shows how product performance is improved by controlling themoisture content within the MDI with the present invention.

[0109] A third comparative stability test at various elevated storageconditions was performed on a batch of Salmeterol/HFA134a Inhalers thatwere overwrapped shortly after manufacture and compared against acontrol of new-overwrapped inhalers from the same batch. The FPM andmoisture determinations are summarized in Table 3 and 4. Table 3 showsthe FPM over six months for the control group non-overwrapped MDIscompared to overwrapped MDIs (contained within the package 22 of thepresent invention). Table 4 shows the inhaler moisture content in PartsPer Million (or PPM) over six months for the control group ofnon-overwrapped meter dose inhalers compared to MDIs provided in thepackage 22 of the present invention.

[0110] The data in Table 3 shows that the fine particulate mass (FPM),measured in micrograms (μg), of the MDIs provided in the package 22 ofthe present invention decreases at a substantially slower rate than thatof the control group of non-overwrapped meter dose inhalers. The data inTable 4 shows that the moisture content in part per million (ppm) oversix months for the MDI provided in the package 22 of the presentinvention is less than the moisture content present adjacent to orwithin the MDIs which are not provided with any overwrap. TABLE 3 FineParticulate Mass (in μg) Time point 40° C./75% RH 25° C./60% RH 25°C./75% RH (months) Control wrapped Control Wrapped Control wrapped 0 9.49.4 9.4 9.4 9.4 9.4 1 7.8 8.6 8.4 8.6 8.4 8.7 3 6.0 7.4 8.3 8.5 8.0 8.36 6.2 7.7 7.5 7.8 7.2 7.8

[0111] TABLE 4 Moisture Content (in ppm) Time point 40° C./75% RH 25°C./60% RH 25° C./75% RH (months) Control wrapped Control Wrapped Controlwrapped 0 81 81 81 81 81 81 1 360 63 194 71 217 93 3 540 29 405 45 43464 6 526 93 446 76 485 47

[0112] A fourth comparative test was performed on a control group ofnon-overwrapped MDIs containing fluticasone propionate/HFA-134a comparedto MDIs of the same drug and propellant provided in the package 22 ofthe present invention. The MDIs of the present invention weremanufactured and provided in the package 22 of the present inventionshortly after the time of manufacture and placed on stability at variouselevated storage conditions along side the control group of unwrappedinhalers from the same batch.

[0113] Table 5 of the fourth test summarizes the variation in thecontent uniformity at the six-month time period in addition to themoisture of the control group and the MDIs provided in the package 22 ofthe present invention. Table 5 shows the variation in content uniformityin percentage of the relative standard deviation (RSD) based on thevalues for a dose ex actuator obtained from ten cans at the end of use(final nominal use). This variation test was obtained over six monthsfor the control group of non-overwrapped MDIs compared with MDIsprovided in the package 22 of the present invention.

[0114] Table 6 shows the inhaler moisture content in parts per millionor PPM over six months for the control group of non-overwrapped MDIs ofthe fluticasone propionate/HFA-134a type compared to MDIs of the samedrug and propellant provided in the package 22 of the present invention.Table 5 demonstrates that the MDIs provided in the package 22 of thepresent invention have a substantially smaller standard deviation inproduct performance so that the MDI will typically have a consistentincreased performance relative to non-overwrapped MDIs.

[0115] Table 6 further shows that the initial moisture content in partsper million for the MDIs 36 provided in the package 22 of the presentinvention significantly and substantially decreases while the moisturecontent of the control group of non-overwrapped MDIs substantiallyincreases from the initial measurement of the moisture content. TABLE 5Time point 40° C./75% RH 30° C./75% RH (months) control wrapped controlWrapped 0 6 6 6 6 3 14 5 11 5 4 12 5 6 12 9

[0116] * RSD (%)=percentage relative standard deviation based on thevalues for dose ex actuator obtained from 10 cans at the end of use(final nominal dose). TABLE 6 Time point 40° C./75% RH 30° C./75% RH(months) control Wrapped control Wrapped 0 198 198 198 198 3 751 50 41261 4 408 83 6 521 30

[0117] Table 7 shows the loss of HFA-134a (in grams) for wrappedAlbuterol 134a MDI's stored for 14 months at 30° C./60%RH and 40°C./75%RH. The data in Table 7 is a mean of 5 determinations from 3separate batches of MDI's. TABLE 7 40° C./75% RH 30° C./60% RH Loss ofHFA134a from the can (g) 0.4 0.7 HFA134a remaining in the pack 0.1 0.2(g)

[0118] The results of the above mentioned tests, outlined by Tables 1-4,prove that loss in fine particulate mass (FPM) of MDIs is directlyrelated to moisture content adjacent or within an MDI. The resultstabulated in Tables 5-7 prove that variation of the content uniformityat the end life of the wrapped MDIs of the present invention issubstantially less than non-wrapped MDIs. Therefore, substantialincreases in product performance of MDIs 36 are possible with thepackage 22 of the present invention which substantially reduces oreliminates the ingression of moisture or water vapor into the enclosedvolume 40. Table 7 shows proof of the operation of the virtual one wayvalve mechanism that permits egression of HFA-134a from package 22.

[0119] The invention being thus described, it will be obvious that thesame may be varied in many ways. Such variations are not to be regardedas a departure from the spirit and scope of the invention, and all suchmodifications as would be obvious to one skilled in the art are intendedto be included within the scope of the following claims.

[0120] Another experiment focused on three types of foil pouches havingan aluminum component providing a moisture barrier. For Foil pouches1-3, the desiccant included calcium sulfate, silica gel, 4A molecularsieve and casein/glycerol.

[0121] Foil pouch 1 was constructed from a 9 μm aluminum foil layer.Foil pouch 1 also included a one-way valve to allow any propellantleaking from the enclosed MDI to egress from the pouch. Foil pouch 1 isavailable from Raackmann UK Ltd. as coextruded oriented polypropylene(20 μm), adhesive, polyester (PETP)(12 μm), adhesive, aluminum foil (9μm), adhesive, polyethylene (60 μm).

[0122] Foil pouch 2 was constructed from a 25 μm aluminum foil layer.Foil pouch 2 is available from Raackmann UK Ltd. as ZANTAC® EFFERdose®Foil, Ref. DMF#1156, Polyester (PET) 0.48 mils, primer, whitecopolyethylene 0.50 mils, aluminum foil 1.0 mils (25 μm), copolymer 0.5mils, linear low density polyethylene.

[0123] Foil pouch 3 was constructed from a 12.7 μm aluminum foil layer.Foil pouch 3 is available from Allusuisse/Laminated Films and Packaging(LF15015) polyester (48 gauge), adhesive, aluminum foil (0.0005 inches,12.7 μm, adhesive, linear low density polyethylene film (4 mil). Noone-way valve was present in foil pouches 2 or 3.

[0124] An MDI containing an aerosol formulation of albuterol sulfate inHFC 134a propellant was used. The desiccant used was a 10 gram silicagel pack. The control was an identical MDI without a pouch or desiccant.The moisture content was assessed initially and after 1 m and 3 mstorage at 40° C./85%RH. Moisture analysis was performed using KarlFischer Coulometric Titration. The mean results for initial and 3 mstorage is shown in Table 8. TABLE 8 Moisture Content Results for FoilPouches 1-3 with Albuterol Sulfate/HFC 134a MDI's MEAN MOISTURE STORAGEAT CONTENT (PPM) 40° C./ AFTER 85% RH FOIL POUCH PACKAGING Initial 3months No. 1 control 146 545 No. 1 with desiccant 146 179 No. 1 withoutdesiccant 146 431 No. 2 control 180 565 No. 2 with desiccant 180 160 No.2 without desiccant 180 337 No. 3 control 204 365 No. 3 with desiccant204 87 No. 3 without desiccant 204 216

[0125] The results shown in table 8 clearly show that foil packagingsystems with down to at least 9 μm aluminum foil are effective inreducing moisture ingress into the MDI when used in combination with adesiccant.

[0126] Foil pouch 3 from Table 8 was also evaluated using vacuum sealingand nitrogen purging in lieu of a desiccant. The results are shown inTable 9. TABLE 9 Moisture Content Results for Vacuum Sealed and NitrogenPurged Systems with MDI Containing Albuterol Sulfate/HFC 134a afterstorage at Mean Moisture 40° C./ Moisture Protection Content (ppm) 85%RH System INITIAL 1 MONTH 3 MONTHS Control 125 301 448 Nitrogen PurgedPouch 125 176 216 Vacuum Sealed Pouch 125 197 252 Foil Pouch 3 Plus 125149 144 Desiccant

[0127] The results in Table 9 show that the nitrogen purging and vacuumsealing embodiments substantially reduce the rate of moisture ingress ascompared to the control having no pouch. Moreover, the resultsdemonstrate that nitrogen purging or vacuum sealing the pouch when usedin combination with a desiccant would still further reduce the rate ofmoisture ingress.

We claim:
 1. A drug product comprising: a drug formulation comprising amixture of one or more drugs and one or more hydrofluoroalkanepropellant; a pressurized container containing the drug formulation; adesiccant; and, a pouch constructed from a material comprising ametallic foil layer, wherein the pressurized container and the desiccantare contained within the pouch.
 2. The drug product of claim 1, whereinthe drug is selected from the group consisting of fluticasone,beclomethasone, salmeterol, albuterol, ipratropium, salts, esters orsolvates thereof, and combinations thereof.
 3. The drug product of claim2, wherein the drug is a combination of salmeterol xinafoate andfluticasone propionate.
 4. The drug product of claim 2, wherein the drugis a combination of salmeterol and ipratropium.
 5. The drug product ofclaim 2, wherein the drug is fluticasone propionate.
 6. The drug productof claim 2, wherein the drug is salmeterol xinafoate.
 7. The drugproduct of claim 2, wherein the drug is beclomethasone dipropionate. 8.The drug product of claim 2, wherein the drug is albuterol sulfate. 9.The drug product of claim 1, wherein the propellant is a member selectedfrom the group consisting of 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane and combinations thereof.
 10. Thedrug product of claim 1, wherein the propellant is1,1,1,2-tetrafluoroethane.
 11. The drug product of claim 1, wherein thedrug formulation consists essentially of one or more drugs and one ormore hydrofluoroalkane propellants.
 12. The drug product of claim 1,wherein the drug formulation consists of one or more drugs and one ormore hydrofluoroalkane propellants.
 13. The drug product of claim 1,further comprising one or more excipients.
 14. The drug product of claim13, wherein the one or more excipients is selected from the groupconsisting of surfactants, preservatives, flavorings, antioxidants,antiaggregating agents, cosolvents and combinations thereof.
 15. Thedrug product of claim 14, comprising 0.01-5% w/w of one or morecosolvents, wherein the surfactant is a C₂₋₆ aliphatic alcohol or apolyol.
 16. The drug product of claim 15, comprising 0.1-5% w/w of oneor more cosolvents.
 17. The drug product of claim 15, comprising 0.1-1%w/w of one or more cosolvents.
 18. The drug product of claim 15, whereinthe cosolvent is gylcerol, ethanol, isopropanol or propylene glycol. 19.The drug product of claim 15, wherein the cosolvent is ethanol.
 20. Thedrug product of claim 14, comprising 0.05-5% w/w of one or moresurfactants.
 21. The drug product of claim 1, wherein the pressurizedcontainer is a metered dose inhaler.
 22. The drug product of claim 1,wherein the metallic foil layer is aluminum.
 23. The drug product ofclaim 22, wherein the aluminum foil layer has a thickness of about 12.7μm.
 24. The drug product of claim 22, wherein the aluminum foil layerhas a thickness in the range of 9-25 μm.
 25. The drug product of claim1, wherein the desiccant includes 10 g silica gel in a pack.
 26. Thedrug product of claim 1, wherein the pouch is vacuum sealed.
 27. Thedrug product of claim 1, wherein the pouch is purged with nitrogen gas.28. The drug product of claim 22, wherein the pouch is constructed froma multi-layer laminate film comprising a polymeric outer protectivelayer adhesively laminated to the metallic foil layer laminated to apolymeric inner heat seal layer.
 29. The drug product of claim 28,wherein the protective layer is constructed from a polyester.
 30. Thedrug product of claim 28, wherein the inner heat seal layer isconstructed from an ionomer resin.
 31. The drug product of claim 28,wherein the inner heat seal layer is constructed from a polyethylene.32. The drug product of claim 29, wherein the protective layer has athickness in the range of 1-40 μm.
 33. The drug product of claim 32,wherein the protective layer has a thickness in the range of 4-30 μm.34. The drug product of claim 33, wherein the protective layer has athickness in the range of 10-23 μm.
 35. The drug product of claim 34,wherein the protective layer has a thickness of 12 μm.
 36. The drugproduct of claim 28, wherein the metallic foil layer has a thickness inthe range of 1-100 μm.
 37. The drug product of claim 28, wherein themetallic foil layer has a thickness in the range of 3-70 μm.
 38. Thedrug product of claim 28, wherein the metallic foil layer has athickness in the range of 5-50 μm.
 39. The drug product of claim 28,wherein the metallic foil layer has a thickness in the range of 6-20 μm.40. The drug product of claim 28, wherein the metallic foil layer has athickness of 9 μm.
 41. The drug product of claim 28, wherein the heatseal layer has a thickness in the range of 1-100 μm.
 42. The drugproduct of claim 28, wherein the heat seal layer has a thickness in therange of 5-70 μm.
 43. The drug product of claim 28, wherein the heatseal layer has a thickness in the range of 10-60 μm.
 44. The drugproduct of claim 28, wherein the heat seal layer has a thickness in therange of 25-55 μm.
 45. The drug product of claim 28, wherein the heatseal layer has a thickness in the range of 25-50 μm.
 46. The drugproduct of claim 28, wherein the heat seal layer has a thickness of 50μm.